Although gliomas and glioblastomas are not the most commonly occurring cancers — there are about 10,000 new cases in the United States each year — they are among the most deadly. The median survival of people diagnosed with these cancers is between 12 and 15 months.

However, a recent article in The New York Times estimated that the percentage of patients who survive two years from diagnosis of glioblastoma has more than tripled in the last five years, from 8% to 25%, largely because of the use of temozolomide (Temodar, Schering Plough) plus radiation as part of treatment regimens. That, in addition to progress made with bevacizumab (Avastin, Genentech), an antiangiogenic VEGF inhibitor, means that research and treatment options from gliomas are more exciting now than they have been for the last 20 years, according to Howard Fine, MD.

“I’ve been treating glioblastoma for about 22 years. I’ve taken care of more than 20,000 patients,” said Fine, chief of the neuro-oncology branch at the National Cancer Institute’s Center for Cancer Research and of the National Institute of Neurologic Disorders and Stroke. “The kinds of things we’ve seen in the clinic in the last four years blows away anything I saw in the previous 18 years of my career.”

Bevacizumab was granted accelerated approval for the treatment of patients with relapsed glioblastoma in May. In addition to gains in two-year survival seen with the use of temozolomide, results from several phase-2 studies of bevacizumab have shown improvements in PFS and objective response rates.

Traditionally, six-month PFS survival in relapsed or progressive glioblastoma is about 9% to 21%, and objective response is less than 10%. According to results published in the Journal of Clinical Oncology in October, patients with recurrent glioblastoma had an estimated six-month PFS of 42.6% while assigned to bevacizumab alone and 50.3% while assigned to bevacizumab plus irinotecan.

Henry S. Friedman, MD, and colleagues who conducted the study said the PFS exceeded the expected 15% rate assumed for salvage chemotherapy and irinotecan alone. Furthermore, the objective response rate was 28.2% in the bevacizumab group and 37.8% in the bevacizumab plus irinotecan group.

Despite these promising results, much remains to be seen regarding treatment with bevacizumab, according to Patrick Y. Wen, MD, associate professor of neurology at Harvard Medical School. Wen published an editorial in Expert Review of Anticancer Therapy in September. In it, he wrote that bevacizumab’s cost is an economic issue that needs to be resolved, that although bevecizumab clearly has benefits, they may be transient, and that the improved PFS associated with the drug may not always translate into improved OS.

Bevacizumab and similar drugs clearly shrink tumors, Wen told HemOnc Today, but they have not been shown to destroy tumors. “Trying to understand the mechanisms of resistance to improve on these therapies has been a real challenge,” he said. “That’s probably the hottest area in neuro-oncology right now.”

Immunology

In addition to the more standard temozolomide and the newly approved bevacizumab, there are several other therapies, such as vaccines and targeted molecular therapies, which are giving hope to the experts who spoke to HemOnc Today. Friedman, the James B. Powell Jr. Professor of Neuro-Oncology at Duke University, said medical science could be on the cusp of a cure.

“I believe that temozolomide made a small step forward. I believe bevacizumab will make an even bigger step forward, and I believe vaccines will make another step forward,” Friedman said. “There is an ever increasing minority of patients who appear to get cured of this disease. Within the next five years, I hope to see a major increase in survival that is bevacizumab-mediated, and maybe vaccine-mediated as well.”

In 2008, Wheeler and colleagues published results in Cancer Research from a phase-2 trial of a glioblastoma multiforme vaccine. Thirty-four patients with glioblastoma and 10 healthy participants were assigned to vaccination with autologous tumor lysate-pulsed dendritic cells at Cedars-Sinai Medical Center. Researchers said they hoped that the vaccine would stimulate the host immune system to mount a specific cytotoxic T-lymphocyte response against mesothelioma tumor cells, resulting in tumor cell lysis. Primary endpoints were time to progression and time to survival.

Time to survival in patients who responded to the vaccine was 642 days compared with 430 days in nonresponders. Time to progression was 308 days in vaccine responders compared with 167 days in nonresponders. The researchers found that time to survival and time to progression in all vaccinated patients with glioblastoma compared favorably to patients treated with nonvaccine therapies at Cedars-Sinai during the course of the trial.

As in earlier studies, the vaccine was found to be safe and well-tolerated; there were no grade-3 or grade-4 adverse reactions reported.

“Our findings validate post-vaccine chemosensitization of glioblastoma multiforme by vaccine-induced T-cell responses,” Wheeler and colleages wrote. “It should be noted that these findings, although promising, require verification in larger groups of patients treated in randomized trials. Nevertheless, based on this promise, it is anticipated that screening vaccine candidates for markers predicting vaccine responsiveness, combining vaccination with recently improved chemotherapeutic regimens, and rendering vaccines accessible to more patients may help maximize vaccine-mediated clinical benefits for glioblastoma multiforme.”

Among the current studies into immunotherapies for glioblastoma, researchers at The University of Texas M.D. Anderson Cancer Center are currently conducting a trial looking at WP1066, an orally delivered STAT3 inhibitor. The ultimate goal is to determine if inhibition of STAT3 might directly kill glioblastoma cells and stimulate the immune system to attack those tumor cells.

Friedman said there are several vaccines undergoing clinical trial. Pfizer’s CDX-110, a glioma-associated antigen peptide-pulsed autologous dendritic cell vaccine, is being researched by Linda M. Liau, MD, PhD, at Jonsson Comprehensive Cancer Center at UCLA. Another is the attenuated cytomegalovirus vaccine being developed at Duke. Friedman said he hopes that, because vaccines represent a different strategy for attacking glioblastoma, at least one vaccine will eventually enter clinical practice.

Wai-Kwan Alfred Yung, MD, chair of neuro-oncology at M.D. Anderson Cancer Center, said he is sure vaccines will prove a viable strategy in the near future.

“Immunotherapy should be on our radar screen. We should probably put more effort and more science into exploring vaccines,” he said. “There are many ongoing trials looking into vaccines, but the early results don’t show any one vaccine standing out.”

Molecularly targeted therapies

Fine said that the most hope for a cure may lie in molecularly targeted agents. Molecularly targeted therapies reflect the reality that cancer cells are different than normal cells due to mutation, so this class of drugs is selective against the cancer cell and not the normal cell.

“That theory has been around for a long time, but for the first time we’re actually seeing evidence, not just in our mice and our rat studies but in our patient studies, that these kinds of agents can actually change the course of this disease and cause tumors to regress in a way I’ve never seen before,” Fine said. “They represent a more rational way of treating cancer as opposed to in the past and still today, where standard treatment for cancer is made up of poisons — be it standard cytotoxic agents, chemotherapy agents or radiation.”

The VEGF inhibitor bevacizumab seems to be the best-known and most-tested treatment of this group. Phase-2 studies have shown that alone and in combination with irinotecan, bevacizumab was effective and well-tolerated in patients with glioblastomas.

The epidermal growth factor receptor is amplified in roughly 50% of glioblastomas and over-expressed in many malignant gliomas regardless of amplification status, and results have shown that the presence of EGFRvIII is an independent prognostic factor for poor survival. This would seem to suggest a role for EGFR in glioma pathogenesis and offer an obvious rationale for developing therapies that target EGFR.

However, Sathornsumetee and colleagues concluded after studying the existing literature that the EGFR kinase inhibitor gefitinib (Iressa, AstraZeneca) had minimal impact on radiographic response. Results of studies evaluating another EGFR kinase inhibitor, erlotinib (Tarceva, OSI), showed response rates from 6% to 25%, but neither drug had a clear impact on survival.

“We’ve done trials for erlotinib in glioma and there’s about a 10% response rate. But just having the presence of the EGFR or having an active EGFR on the tumor cells is not enough to predict who those 10% of responders are. It’s much, much more complex than that,” Fine said. “We’re not yet at the point where we understand that complexity. It’s more than just finding the right biomarker to select the right patients for the right drug. Finding that biomarker that identifies what will predict for response to these agents is still a tremendous work in progress.”

Molecular pathways

The other target for molecular therapies is finding treatments that attack the molecular pathways that sustain tumors. Wen said that because tumor stem cells are of particular importance in glioblastomas, understanding the pathways that drive those stem cells is crucial to treating this disease.

Currently, trials are exploring inhibitors of the Notch pathway and the hedgehog pathway, Wen said. “There’s a transcription factor called OLIG2 that’s thought to be very important in glioma stem cells. Finding ways to knock down OLIG2 is an important therapeutic strategy, but that’s not clinically available right now.”

According to Fine, targeting pathways represents a new way of treating cancer.

“There’s a whole set of developmental pathways that our colleagues in developmental biology have known about for years but that were never in the repertoire of cancer biologists and so were never in the repertoire of pharmaceutical companies that think about targeting cancer pathways,” he said. “All of a sudden, there’s this great convergence of developmental and stem cell biology pathways with cancer pathways. It opens up a whole new series of molecular targets such as Wnt, sonic hedgehog and Notch.”

Perifosine (Keryx Biopharmaceuticals), an oral ATK inhibitor, is currently under evaluation for use in patients with malignant gliomas. Sirolimus (Rapamycin, Wyeth) and its synthesized analogs, temsirolimus (Torisel, Wyeth), everolimus (Afinitor, Novartis), and AP23573 (Ariad Pharmaceuticals) have been evaluated in clinical trials of malignant gliomas as inhibitors for mTOR, a serine/threonine kinase downstream from AKT.

“Preclinical studies demonstrated that inhibition of mTOR can stimulate the kinase activity of its immediate upstream effector, AKT, which may decrease the antitumor efficacy,” Sathornsumetee and colleagues wrote in Cancer in 2007. “PI-103, a novel inhibitor of both PI3K and mTOR, has shown promising activity in both in vitro and in vivo models of malignant gliomas, partly because of blocking activated PI3K/AKT induced by mTOR inhibition.”

Sathornsumetee and colleagues wrote that studies conducted by the North American Brain Tumor Consortium and the North Central Cancer Treatment Group have shown evidence that temsirolimus is associated with radiographic improvement, but that has not translated into improved survival.

“Targeting molecular pathways is very promising because we now have a lot more information on each tumor that might be utilizing the growth signal,” Yung said. “We will increase our efficacy when we learn how to classify them better so we can cater a drug to a specific group of tumors.”

Designing effective trials

The experts who spoke to HemOnc Today all cited the difficulty of designing randomized, controlled trials to investigate glioma treatments. Because the disease is highly heterogeneous, each patient in many ways represents a separate trial. Fine noted that it is becoming a priority to consider new paradigms of clinical trial design to address the tremendous heterogeneous nature of this disease so that each clinical trial for a glioblastoma therapy does not take decades or millions of dollars to conduct.

“If it was simple, all you’d do is screen patients for, say mutation B, and design a trial of patients who just have mutation B,” he said. “The problem is it’s not all that simple. These molecularly targeted agents don’t always just identify mutation B. They may be effective against mutation B, but only when you have mutations A and G, but normal gene X. It’s a highly complex system and one we don’t yet understand.

“Unfortunately, it may turn out that we may have to do trials the old fashioned way and take all comers, then retrospectively look at that 10% of patients who respond and find out what was unique about them and their tumors before you can identify the probable predictors of responsiveness, and then design a prospective trial with people who have just those markers in order to prospectively confirm the observation,” Fine said.

Eventually, study populations will be tightly screened, Friedman said. Physicians will identify certain key pathways and only enroll patients who have abnormalities.

“Study populations will be much more homogeneous,” he said. “That’s the hope of the future. That’s not the future right now.”

Yung said that all solid tumors are heterogeneous, yet researchers have figured out how to design effective trials to evaluate treatments for lung cancer and breast cancer.

“No two glioblastomas are the same, but give me 100 glioblastomas and there may be three or four different groups and each group may respond to a different targeting agent,” he said. “We have to learn how to match the signal from the tumor to the signaling agent we need to use.”

Ultimately, the experts agreed that, for the first time in a long time, the trends in glioblastoma treatment are moving in the right direction.

“We have made some small steps. I am very happy to see that we’re having more long-term survivors. We’re bending the tail end of the curve more and more,” Yung said. “We’re close to moving the median survival in a substantial way. I don’t know whether we can use the word breakthrough, but I think we’re on the verge of making some major improvements.” – by Jason Harris

ScienceDaily (June 6, 2010) — Researchers from St. Jude Children's Research Hospital and the Pediatric Brain Tumor Consortium (PBTC) presented at the American Society of Clinical Oncology the findings of a pediatric brain tumor study using an experimental drug that targets the underlying genetic makeup of the tumor. The research focused on a new way to attack the tumors by blocking the Hedgehog pathway that is linked to approximately 20 percent of medulloblastomas.

The study is the first to report that the drug can be safely administered to children. The study also suggested that the drug is showing early signs of efficacy in this patient population, with some children still on treatment almost a year with no progression of disease. All the children on this study had medulloblastomas that persisted or returned despite standard treatment with radiation and chemotherapy. Recurrent medulloblastoma currently has a cure rate of less than 5 percent.

The researchers found that patients whose tumors had the Hedgehog molecular pathway activated appear to be some of the same patients who have responded to treatment in this trial, based on length of time on study. Investigators have observed tumor responses in similar young adult patients whose tumors had the Hedgehog molecular pathway activated. These early findings have given the green light for pediatric research to advance to a larger Phase II study scheduled to open later this year, and to increase the number of patients on the young adult study.

The Phase I study (PBTC -025) included 13 patients, 12 of them evaluable, ranging in age from 4 to 21 years. All received one of two different doses of GDC-0449 daily for a minimum of 28 days and continued on treatment for as long as their disease remained stable. In addition to determining the safety and dosing of this experimental drug for children, the trial also conducted extensive research into pathologic and genomic methods for better identifying tumors that have the Hedgehog pathway activated.

"Medulloblastomas are the most common malignant brain tumors in children," said Amar Gajjar, M.D., co-chair of the St. Jude Department of Oncology and principal investigator of the PBTC trial. "The trend in treating children with these cancers is toward targeted therapies like this one, which block key signaling pathways and disable the cancer's ability to function or reproduce. We know that this Hedgehog pathway is important in the growth of these especially hard-to-treat tumors."

The PBTC has an ongoing Phase II trial in recurrent medulloblastomas in young adults (age 22 and older), with this same agent, which has recently been expanded to include more patients. A Phase II trial of GDC-0449's effectiveness against recurrent medulloblastomas in children (up to age 21) will start later this year based on the results of today's reported Phase I trial.

All of the PBTC trials are being sponsored by the Division of Cancer Treatment and Diagnosis, National Cancer Institute (NCI) under a Cooperative Research and Development Agreement Letter of Intent between NCI and Genentech, Inc.

St. Jude is home to the nation's largest research-based pediatric brain tumor program. St. Jude investigators have played a pivotal role in advancing understanding of the molecular missteps that give rise to medulloblastomas as well as seeking new, more targeted therapies to combat the tumors. St. Jude investigators have published evidence that targeting the Hedgehog pathway eradicated medulloblastomas in laboratory models. During fetal development the Hedgehog pathway plays a central role in normal growth of the cerebellum. The cerebellum is located at the base of the skull and is the structure that helps coordinate movement and plays a role in mastering balance and other motor skills. Medulloblastomas begin in the cerebellum, and uncontrolled activity along this pathway is linked to several cancers, including basal cell skin cancer.

ScienceDaily (June 4, 2010) — Patients with high-grade gliomas who experience acute (early) neurological toxicity during their treatment were more likely to experience chronic (late) neurological toxicity and shortened overall survival, according to researchers from the Kimmel Cancer Center at Jefferson.

The study will be presented at the 2010 ASCO Annual Meeting in Chicago (Abstract #2037).

Yaacov Lawrence, M.D., assistant professor of Radiation Oncology at Jefferson Medical College of Thomas Jefferson University, and colleagues at the Radiation Therapy Oncology Group (RTOG) used the RTOG database to identify 2,610 patients with high-grade glioma who participated in clinical trials from 1983 to 2003. Toxicity and outcome data were analyzed for all subjects.

All of the patients had received fractionated radiation therapy to treat their brain cancers. The researchers observed 182 acute neurological toxicity events. On a multivariate analysis, poor performance status, more aggressive surgery, poor neurological function and cognitive impairment were associated with increased acute neurological toxicity.

Acute neurological toxicity was significantly associated with chronic neurological toxicity. It was also found to predict overall survival: 7.8 months in patients who experienced acute neurological toxicity vs. 11.8 months in patients who did not.

"As brain tumor patients begin living longer thanks to modern therapeutics, treatment-related side effects become more important," Dr. Lawrence said. "Traditional cancer trials have emphasized tumor control as a means to increase overall survival. Our study emphasizes the association of treatment side effects with long-term outcomes. This novel finding is yet to be fully explained. The bottom line is that we have to be especially careful with patients who experience significant toxicity during treatment. Conversely, we can reassure those patients who have a smooth ride through radiation therapy that they are likely to do above average."

Amarillo, Texas - More people in the Texas Panhandle are beating cancer than in years past.

Close to 600 cancer survivors came out on Friday to celebrate National Cancer Survivors Day at the Harrington Cancer Center.

We're told the event grows every year... In fact, it's grown so much since it first began that they outgrew the original location on the center's front porch, so they recently moved it to the back parking lot.

That, in and of itself, speaks volumes about the great strides that are being made in cancer research. CEO Paul Hancock says, "There are a lot of people in the past who might have died from their diagnosis in a relatively short amount of time, and now more of those people are cured. And even the ones who aren't cured are living longer with the diagnosis of cancer. So that's been one of the big advances. There are more treatments available that keep people alive and keep them living a good quality life for a longer period of time."

Survival rates have jumped about 11%in the past few years. The three most common types of cancer Harrington sees are breast, colon and lung cancer.

Everyone we spoke with today said they came out to celebrate how lucky they are to be alive, honor those who weren't as lucky, and hope for further research so even more people can attend the event next year.

Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis-median overall survival is in the range 12-15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3-4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard fotemustine schedule.

ScienceDaily (June 21, 2010) — Researchers at the University of Leicester and the University of Ferrara in Italy have collaborated to develop new drugs which have the potential to relieve cancer pain without causing many of the side effects of current pain-treatments like morphine.

Figures show that 90% of cancer patients experience pain in the final year of their lives and this is a big problem. Currently, the use of drugs like morphine produces side effects such as depressed breathing, drowsiness, constipation and tolerance. Unfortunately tolerance usually results in an increased dose of morphine, which in turn means that patients experience more of these side effects.

Professors David Lambert and David Rowbotham at the University of Leicester, as well as Doctors Guerrini, Calo and Professor Salvadori from the University of Ferrara in Italy, are leading the early experiments of a new group of drugs which may not produce these side effects. The research done at the University of Leicester has been funded by the Leicestershire and Rutland charity Hope Against Cancer.

Professor David Lambert commented: "This work is still at a very early stage but has the potential to change the way we think about making drugs for pain related issues."

The new group of drugs, which were developed in the University of Ferrara and tested by the University of Leicester, is designed to produce pain relief by acting at two targets simultaneously. The two target idea may provide effective pain relief with less tolerance.

Hope Against Cancer has funded this 3-year PhD project at the University of Leicester to look at the long term effects of these new drugs, with a primary focus on drug tolerance.

Nikolaos Dietis, the PhD research student who is currently working on the project, said:

"Tolerance to strong painkillers like morphine involves complicated biological processes, aspects of which still remain questionable. Our research may provide some answers by designing new drugs that have multiple roles. We are now studying these drugs to see what they do in the long-term."

Dr Guerrini said: "Pain is a very complicated condition, whose control and relief could be achieved with the use of drugs that act on two different targets in order to obtain pain relief more effectively."

The project at the University of Leicester could lead to further development of these new drugs that could even lead to future trials on cancer patients.

Professor Rowbotham commented: "We need to further refine this work to enable studies to be performed in patients. This may be a relatively long-term process, but it offers a completely new approach to pain management for cancer patients in the future."

RICHLAND, Wash., Jun 23, 2010 (BUSINESS WIRE) -- IsoRay, Inc. (ISR 1.51, +0.04, +2.72%) announced today that it has completed a license agreement with Hologic, Inc. (HOLX 14.68, -0.21, -1.41%)for exclusive worldwide distribution rights to the GliaSite(R) radiation therapy system, the world's only FDA-cleared balloon catheter device used in the treatment of brain cancer. The system's balloon catheter is a landmark technology that allows physicians to treat more patients than ever before with brachytherapy or internal radiation and provides important benefits over other radiation treatment options.

Brain cancer presents unique treatment challenges. Brain tumors are very often difficult to remove completely because of the need to avoid damaging the brain. Further, tumors tend to spread to healthy parts of the brain. Typically, surgeons remove as much as they can of the tumor and then treat the areas surrounding where the tumor was removed with radiation therapy. They sometimes use chemotherapy as well. However, most cancerous brain tumors reoccur shortly following removal, and the cancer tends to return near the site of the original tumor. Brain cancer is one of the fastest growing cancers and recurrence often proves fatal.

The GliaSite system offers a number of advantages in brain cancer treatment. It places a specified high dose of a liquid radiation source in the areas most likely to contain cancer after brain tumor removal and is less likely to damage healthy brain tissue. It helps eliminate the ability for the tumor to reoccur, which in turn impacts patient longevity.

In a related major development, IsoRay is moving forward with the regulatory approval process for its new liquid form of Cesium-131, an exciting advance in brachytherapy for the treatment of brain cancer, that would be delivered using the GliaSite radiation therapy system.

IsoRay CEO Dwight Babcock said physicians have voiced strong support for the GliaSite system and liquid Cesium-131 combination because they recognize the benefits afforded their patients. "In America alone, more than 200,000 men, women, and children are diagnosed with brain cancers every year. The GliaSite therapy system and its use to deliver a liquid radiation source is a versatile, effective treatment for numerous brain cancers," he said.

Cesium-131 brachytherapy is a patented internal radiation therapy that has several advantages over older radioactive isotopes including faster delivery of a radiation dose that allows less time and opportunity for the cancer cells to repopulate and has a soft energy that minimizes radiation exposure for the operating room and support staff as well as the patient's family members.

Babcock said this is another step forward in IsoRay's efforts to advance cancer treatment. "Progress spells hope for patients and the physicians who help them. The GliaSite system represents further achievement as we work toward our goal of expanding brachytherapy solutions throughout the entire body and improving outcomes for cancer patients," said Babcock.

Previously, approximately 500 GliaSite cases were performed annually at some 40 hospitals worldwide. GliaSite therapy has established reimbursement for both in-patient and out-patient settings.

Invention Enables People With Disabilities Communicate and Steer a Wheelchair by Sniffing

ScienceDaily (July 27, 2010) — A unique device based on sniffing -- inhaling and exhaling through the nose -- might enable numerous disabled people to navigate wheelchairs or communicate with their loved ones. Sniffing technology might even be used in the future to create a sort of 'third hand,' to assist healthy surgeons or pilots.

Developed by Prof. Noam Sobel, electronics engineers Dr. Anton Plotkin and Aharon Weissbrod and research student Lee Sela in the Weizmann Institute's Neurobiology Department, the new system identifies changes in air pressure inside the nostrils and translates these into electrical signals. The device was tested on healthy volunteers as well as quadriplegics, and the results showed that the method is easily mastered. Users were able to navigate a wheelchair around a complex path or play a computer game with nearly the speed and accuracy of a mouse or joystick.

Sobel explains: "The most stirring tests were those we did with locked-in syndrome patients. These are people with unimpaired cognitive function who are completely paralyzed -- 'locked into' their bodies. With the new system, they were able to communicate with family members, and even initiate communication with the outside. Some wrote poignant messages to their loved ones, sharing with them, for the first time in a very long time, their thoughts and feelings." Four of those who participated in the experiments are already using the new writing system, and Yeda Research and Development Company, Ltd. -- the technology transfer arm of the Weizmann Institute -- is investigating the possibilities for developing and distributing the technology.

Sniffing is a precise motor skill that is controlled, in part, by the soft palate -- the flexible divider that moves to direct air in or out through the mouth or nose. The soft palate is controlled by several nerves that connect to it directly through the braincase. This close link led Sobel and his scientific team to theorize that the ability to sniff -- that is, to control soft palate movement -- might be preserved even in the most acute cases of paralysis. Functional magnetic resonance imaging (fMRI) lent support to the idea, showing that a number of brain areas contribute to soft palate control. This imaging revealed a significant overlap between soft palate control and the language areas of the brain, hinting to the scientists that the use of sniffing to communicate might be learned intuitively.

To test their theory, the researchers created a device with a sensor that fits on the nostril's opening and measures changes in air pressure. For patients on respirators, they developed a passive version of the device, which diverts airflow to the patient's nostrils. About 75% of the subjects on respirators were able to control their soft palate movement to operate the device. Initial tests, carried out with healthy volunteers, showed that the device compared favorably with a mouse or joystick for playing computer games. In the next stage, carried out in collaboration with Prof. Nachum Soroker of Loewenstein Hospital Rehabilitation Center in Raanana, quadriplegics and locked-in patients tested the device.

One patient who had been locked in for seven months following a stroke learned to use the device over a period of several days, writing her first message to her family. Another, who had been locked in since a traffic accident 18 years earlier wrote that the new device was much easier to use than one based on blinking. Another ten patients, all quadriplegics, succeeded in operating a computer and writing messages through sniffing.

In addition to communication, the device can function as a sort of steering mechanism for wheelchairs: Two successive sniffs in tell it to go forward, two out mean reverse, out and then in turn it left, and in and out turn it right. After fifteen minutes of practice, a subject who is paralyzed from the neck down managed to navigate a wheelchair through a complex route -- sharp turns and all -- as well as a non-disabled volunteer.

Sniffs can be in or out, strong or shallow, long or short; and this gives the device's developers the opportunity to create a complex 'language' with multiple signals. The new system is relatively inexpensive to produce, and simple and quick to learn to operate in comparison with other brain-machine interfaces. Sobel believes that this invention may not only bring new hope to severely disabled people, but it could be useful in other areas, for instance as a control for a 'third arm' for surgeons and pilots.

When it comes to cancer treatment, most patients would hope to get the latest medications, delivered in line with the world's best practice. But new research from Melbourne's Peter MacCallum Cancer Centre suggests that's not happening. In fact, it's the opposite in many cases.

The researchers took part in a massive study of 853 patients from 16 countries, including Australia. All patients had head and neck cancers. Researchers wanted to compare patients who received chemotherapy and radiation treatment with those given both treatments and a new drug.

To assess the impact of the new drug, they had to make sure all patients were getting good quality radiation treatment.

What they found surprised them. They discovered it was the quality of the radiation treatment that patients received which made a huge difference to their outcomes and survival. Study author Professor Lester Peters found that deviating from the guidelines when giving radiation had a major impact.

"More than one quarter of 'cancer treatment' plans submitted didn't comply with protocols. Those who received inferior radiotherapy had a markedly poorer outcome," he said. In fact, almost 100 patients had treatment plans with significant deficiencies that "would have a likely impact on tumour control".

Even when flaws in treatment plans were pointed out, none of the changes were made which would bring it into line with world's best practice.

Researchers could even quantify the effect, saying that patients who were not getting treatment in line with the guidelines only had a 50 per cent survival rate compared to 70 per cent in the rest of the population. Getting proper radiation made much more difference than the new drug they were testing. The study found impact of poor radiotherapy greatly exceeded the anticipated benefits of concurrent chemotherapy.

So why aren't some cancer patients getting treatment in line with guidelines? The authors found that the size of the cancer centre was crucial.

Centres treating small numbers of patients were the major source of problems, according to author Associate Professor Danny Rischin. Patients in large hospitals had a 5 per cent likelihood of getting poor treatment. In centres with smaller numbers, the rate was as high as almost 30 per cent.

So is the answer to treat all cancer patients in larger centres? It's more complicated than that as many patients want to have cancer treatment in a smaller centre, close to home, rather than travel to a large facility. The nature of radiation treatment means that people need to go the hospital every day for weeks to complete their treatment, so convenience does become a concern for patients. Patient demand has seen the growth of many smaller cancer centres around Australia.

Getting the smaller centres in line with world's best practice is the key. Professor Bryan Burmeister is the president of the Trans-Tasman Radiation Oncology Group. He says if cancer centres want to do complex treatments, they need to be able to show that they can do it safely and effectively so that patients do not miss out.

That way, the convenience of having a cancer centre in your suburb doesn't mean that you are going to get less that the best treatment.

The theory of the cancer stem cell (CSC) has generated as much excitement and optimism as perhaps any area of cancer research over the last decade. Biologically, the theory goes, these cells are distinct from the other cells that form the bulk of a tumor in that they can self-perpetuate and produce progenitor cells, the way that traditional stem cells do. The progenitors’ job is then to repopulate tumor cells eradicated by treatments such as chemotherapy or radiation.

But for all the attention and fanfare CSC research has received, the findings reported to date are far from clear-cut, investigators acknowledge. For example, most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. In addition, other researchers haven’t always been able to replicate initially reported findings. (See the sidebar: “Tools of the CSC Trade: Markers and Xenografts.”) And while these tumor-initiating cells, as they are also called, have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large, suggesting that perhaps CSCs aren’t such a privileged breed.

In other words, the idea of just what cancer stem cells are, and their role in different cancers, appears to be changing.

“The [stem cell] model has not been adequately tested in most cancers,” said Dr. Sean Morrison, who directs the Center for Stem Cell Biology at the University of Michigan. “I think that there are some cancers that do clearly follow a cancer stem cell model…But it will be more complicated than what’s been presented so far.”

An Evolving Idea

Unlike the random or “stochastic” model dominant in cancer research, which holds that nearly any cancer cell has the potential to form a tumor, the cancer stem cell model is one of a hierarchical organization, with the pluripotent cancer stem cell sitting ready and able to amass all of the components of the original tumor.

It’s also thought, with some experimental evidence to support it, that CSC pluripotency allows these cells to adapt and to resist chemotherapy, radiation therapy, and even current molecularly targeted therapies. If true, then these treatments may not harm the most lethal tumor cells, those that can lead to a recurrence with the production of a new set of progenitors.

Despite numerous studies published in the last 16 years that identified CSCs for different cancers—including colon, brain, pancreatic, and breast cancer—the consensus among researchers seems to be that the evidence is strongest for the first cancer in which a population of tumor-initiating cells was discovered, acute myeloid leukemia (AML), as well as for other blood cancers.

“The reason why it’s so much stronger for hematologic malignancies is because hematopoiesis research goes back 40 or 50 years and it’s very stem cell-based,” said Dr. Jean Wang, a stem cell researcher at the University of Toronto. “Whereas in solid tumors, there’s less of a foundation for identifying the normal cellular hierarchies and for [cell-surface] markers that identify different populations of cells like stem cells and progenitors.”

Even so, Dr. Wang believes the existence of CSCs is pretty well demonstrated for breast and brain cancers. But, she cautioned, “I don’t know if it applies to all cancers. In a lot [of cancers] it does seem to apply. But most of the markers we have right now are still very rough.”

Despite the evidence for CSC-like cells in a growing number of cancers, the theory clearly has its skeptics, who point to problems such as shortcomings in the mouse xenograft assay and the variable specificity of the cell-surface markers used to demarcate a CSC from a non-CSC.

“I still feel that it’s a concept yet to be proven,” said Dr. Barbara Vonderhaar, who, along with colleagues in NCI’s Center for Cancer Research, recently published a study identifying a population of CSC-like cells in estrogen receptor-negative breast cancer. “It’s certainly a good idea, but it’s only a hypothesis at this point. We still don’t have definitive proof that cancer stem cells exist.”

The CSC concept is “a work in transition,” said Dr. William Matsui, from the Johns Hopkins School of Medicine, whose lab studies the role of stem cells in hematologic cancers. “To me, as a clinical person, the ideal model is one where you can find something that is going to work in humans. We’re far from that.”

Case Study: Melanoma

One of the most well-known studies in the CSC literature came from Dr. Morrison’s lab in 2008. Earlier studies had suggested that, consistent with the CSC model, there was only a rare population of cells from human melanoma tumors that, when injected into mice with compromised immune systems (called NOD/SCID mice), could form new tumors.

But in a study published in Nature, Dr. Morrison’s team tweaked the common experimental approach: they used mice with immune systems that were even more impaired than NOD/SCID mice and waited longer to assess tumor growth. The result: approximately one in four randomly selected single cells taken from a human melanoma sample could form a tumor.

The results “made clear that estimates of the frequency of tumorigenic cells are far more assay-dependent than we realized,” Dr. Morrison said. In addition to factors such as the status of the mouse’s immune system in the experiments, he continued, “there are probably other variables that have a much bigger influence that we still haven’t discovered.” (In AML, it’s worth noting, use of more immunocompromised mice does not significantly increase the number of cells that can form tumors.)

Researchers from Stanford University earlier this month reported in Nature that they had found a marker, CD271, that identified a somewhat unique population of cells that could produce melanoma in highly immunocompromised mice; anywhere from 2.5 percent to 41 percent of cells in their human tumor samples expressed the marker. In additional experiments using similar mice on which human skin was engrafted, only tumor cells with the marker could produce tumors and metastases in the mice. (In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells.)

The fact that a fairly large percentage of the cells from the nine human melanoma tumors used in the study could initiate a tumor reflects a number of things, wrote lead author Dr. Andrew Boiko and colleagues in the Nature paper. Among them, an evolutionary type process selects for the survival of tumor cells that fail to normally differentiate during tumor development.

That might mean that a cancer stem cell isn’t necessarily part of the original tumor, but due to various factors or influences—such as interactions with the immune system or hypoxia—certain tumor cells, maybe many of them, can activate a stem cell-like “program.”

“I’m a firm believer that the microenvironment, the stem cell ‘niche,’ is every bit as important as the cell itself,” Dr. Vonderhaar said. “I don’t know if just any cell can become [a CSC], but there is a hierarchy of cells, and some may be able to function in a stem cell-like manner, and others may not.”

The CSC field itself, Dr. Matsui noted, needs to move more quickly beyond just determining whether these cells can grow tumors on their own, “and ask what other properties they might have that contribute to clinical outcomes.” Those might include their role in problems such as drug resistance or metastasis.

Some of the controversy surrounding CSCs “is a good thing,” Dr. Matsui said, “because it forces us to be more rigorous in our work. The more rigor we can get in the research, the more clinically applicable all of the ideas are going to be.”

All Niki Perry wanted was pieces of her own brain, and she got angrier by the day as she tried to get them.

She needed samples of her brain tumor this spring to enter clinical trials she hoped might save her life.

What she got, she said, was delay and disappointment. Plus insight into what she sees as a new battleground: who controls what happens to tiny bits of tumor tissue saved after surgery. This tissue is growing more precious as scientists unlock its potential to target treatments to a specific person's cancer.

When Perry had surgery in September, she knew better than most patients how valuable the deadly cells in her tumor might be someday.

A frequent participant in brain-cancer message boards and an aficionado of new research, Perry knew she might want to enter a European cancer vaccine clinical trial or seek genetic testing that would require frozen pieces of her tumor. She said she asked her surgeon at Thomas Jefferson University Hospital to freeze some just in case.

Freezing tumor cells in a form that can be used for vaccines or advanced genetic testing is unusual. Doctors always put some of the tumor, preserved in formalin and embedded in wax, in slides and small blocks for diagnosis and later testing. Perry knew she would want that, too.

When in March she requested the frozen tissue and her slides, Perry said she ran into weeks of red tape and a Catch-22. She says Jefferson balked at sending slides to another hospital until she was officially in a trial there. But she needed the tissue to enter the trial. Jefferson finally mailed the slides at the end of May and she picked up the tissue blocks herself at the hospital. To her dismay, she learned there was no frozen tissue.

The 37-year-old South Philadelphia woman, who has had speech problems since the surgery and now communicates more easily by e-mail, wrote that she felt "helpless" and "enraged" as she fought for the tissue. She felt the hospital, which has said it will not comment on her individual case, got "in the way of my trying to save my own life."

Cancer surgeons at Jefferson usually do not freeze tumor tissue, and Peter McCue, who runs Jefferson's anatomic pathology laboratory, said he did not receive instructions to save frozen cells. He said Perry should not have had trouble getting slides.

Perry's experience is unusual, but she says she's seeing more complaints on message boards from patients having trouble getting tissue sent from one hospital to another.

Some doctors agree with her. They say problems with tissue-sharing likely will worsen as the era of "personalized" cancer treatment unfolds. Individualized care is spurring higher demand for tissue, creating nascent tensions between research and treatment. That's making tumor cells a hot commodity, one that patients - bewildered and terrified by a life-threatening diagnosis - often give little thought.

This is where cancer treatment is heading. The trend has huge fiscal, medical, and social implications. Instead of everyone getting the same chemo cocktail, patients will get treatments aimed at specific mutations in their cancer. They can avoid side effects from drugs that won't help them and can avoid paying for expensive treatments that won't work.

Gregory Foltz, a neurosurgeon who directs brain-tumor treatment at Swedish, says genetic profiling done with frozen brain-tumor tissue may identify the most aggressive forms of a disease that can kill in months. That will help patients make key decisions, like whether to quit a job or enroll in a riskier trial. Companies can justify drugs with smaller target markets. One lung-cancer treatment in development, for example, seems to work well, but only for 3 percent of patients.

Tumor tissue is the keystone of the new science, and its use is fraught with complex, unanswered questions. When cancer patients have surgery, they usually sign consent forms allowing their tumor to be used for research, although hospitals say patient needs should trump science. Tumor tissue might not only save a patient's life - or the lives of other patients years later - but reveal scary genetic truths about him, his family, or his ethnic group. You can't legally sell tissue itself, but its secrets might help a drug company make millions.

So who really owns this stuff and has the right to make decisions about it?

You might think the obvious answer is the patient. But that's actually not clear. C. Mitchell Goldman, a health-care lawyer at Duane Morris L.L.P., expects more lawsuits as more uses for tissue emerge.

"There's not a body of settled law around this issue," he said. It's "fertile for litigation once it becomes clear that having control of this tissue for future use will become important."

Penn bioethicist Arthur Caplan thinks hospitals will have to reserve more tissue for patient use. "The notion of 'I-might-want-it-myself' has just emerged in the last few years," he said. "There's no point in having personalized medicine and mapping the genome if you can't get your tissues shipped."

The evolving problem is that doctors and researchers need more tissue now, and in new forms, while there may be less of it. Early detection and needle biopsies have shrunk the size of tumor samples in some diseases, notably breast cancer. Even though brain tumors like Perry's may be large, surgical techniques often yield little usable tissue.

(NaturalNews) Mainstream media coverage of cancer treatments disproportionately covers positive outcomes and aggressive treatments while underreporting on palliative care and death, according to a study conducted by researchers from the University of Pennsylvania and published in the Archives of Internal Medicine.

"Very few news reports about cancer discuss death and dying, and even those that do generally do not mention palliative and hospice care," the researchers wrote.

Palliative care is medical care designed to reduce suffering and improve quality of life but not to cure a disease. It is a major component of care for terminal or hard-to-cure cancers.

The researchers reviewed 436 articles that had appeared in the magazines Newsweek, Parade, People, Redbook and Time, as well as eight daily newspapers in Chicago, New York and Philadelphia. They found that while 32.1 percent of the articles focused on successful treatment of at least one patient, only 7.6 percent covered patients who died or were expected to. Only 2.2 percent addressed both positive and negative outcomes.

Of 216 people mentioned by name in the articles reviewed, 78.7 percent were survivors and only 21.3 percent died. Yet 50 percent of U.S. residents diagnosed with cancer do not survive the disease.

In addition, the researchers found that although many cancer treatments can have serious and even dangerous side effects, only 30 percent of the articles reviewed mentioned the possibility of adverse effects.

Fifty-seven percent of the articles covered only aggressive forms of cancer treatment, yet only 13.1 percent acknowledged that such treatments do not always result in improved survival. Only two of the articles (0.5 percent) mentioned end-of-life care, while only 11 (2.5 percent) mentioned both aggressive treatment and palliative care.

Such skewed coverage gives people a distorted image of their treatment options, the researchers warned.

"Unrealistic information may mislead the public about the trade-offs between attempts at heroic cures and hospice care," they wrote.

TROY — An engineering professor at Rensselaer Polytechnic has received a $100,000 grant for brain cancer research. The grant, awarded by The Goldhirsch Foundation which specializes in funding brain cancer research, will focus on a lethal type of the cancer for which there is currenly no cure.

Pankaj Karande will be focusing on one of the human body’s most powerful defensive tools: the blood-brain barrier. Essentially, it’s a sort of chemical labyrinth that prevents toxins and viruses in the bloodstream from reaching the brain. While this is normally a foolproof security system for the body, it also limits the ability of physicians to deliver drugs directly to the brain, making it harder to treat brain tumors. Karande is leading a research team that is investigating new methods for bypassing the blood-brain and combating the spread of brain cancer.

Karande, an assistant professor in the Department of Chemical and Biological Engineering, is particularly interested in developing treatments for a lethal type of brain cancer called diffuse malignant glioma.

While there are a number of drugs available for treating glioma, getting any drug into the brain is a huge challenge, he said. The blood-brain barrier is made up of protein-lined cells, which are layered together similar to Velcro. Generally, the only molecules that can pass through are certain nutrients and vitamins.

“Nature designed the blood-brain barrier to protect us from harm, and it’s very good at its job. When you attempt to treat patients with brain ailments, the blood-brain barrier recognizes most drugs as foreign molecules and keeps them out,” said Karande. “We’re trying to develop a method to elegantly, safely, and reproducibly open up the blood-brain barrier, so we can introduce drugs into the brain.”

His research team is looking for some sort of a chemical “wedge” that could be used to pry a hole between the layers — just large enough for drug molecules to enter the barrier and get to the brain. The hole would only stay open briefly and would thus repair itself, posing little risk of damage to the brain. The team is using a combination of computer simulations, in-vitro modeling and other techniques to design new chains of amino acids that could serve as this wedge.

Karande, who earned his doctoral degree in chemical from engineering at the University of California at Santa Barbara, believes that if his research team is successful in breaching the blood-brain barrier, it could also have an impact on other conditions such as Alzheimer’s disease, epilepsy and Parkinson’s disease.

Another aspect of his research looks at using non-invasive methods of delivering drugs and vaccines through the skin and into the bloodstream using small patches that can be directly applied to the skin. The key findings of this study were published in the journal “Nature Biotechnology” in 2004. Skin protects the human body in a way that’s similar to the way the blood-brain barrier protects the brain.

Malignant gliomas are the most common subtype of primary brain tumor - and one of the deadliest. Even as doctors make steady progress treating other types of solid tumor cancers, from breast to prostate, the most aggressive form of malignant glioma, called a glioblastoma multiforme or GBM, has steadfastly defied advances in neurosurgery, radiation therapy and various conventional or novel drugs.

But an international team of scientists, headed by researchers at the Ludwig Institute for Cancer Research (LICR) at the University of California, San Diego School of Medicine, reports in the August 15 issue of Genes & Development that they have discovered a new signaling pathway between GBM cells - one that, if ultimately blocked or disrupted, could significantly slow or reduce tumor growth and malignancy.

More than other types of cancer, GBMs are diverse assemblages of cell subtypes featuring great genetic variation. Anti-cancer therapies that target a specific mutation or cellular pathway tend to be less effective against such tumor heterogeneity.

"These myriad genetic alterations may be one of the primary reasons why GBMs are so lethal," said Frank Furnari, PhD, associate professor of medicine at the UCSD School of Medicine and an associate investigator at the San Diego branch of the LICR.

Even with maximum treatment effort, the median patient survival rate for a diagnosed GBM is nine to 12 months - a statistic that has not changed substantially in decades.

However, Furnari, along with postdoctoral fellows Maria-del-Mar Inda and Rudy Bonavia, and Webster Cavenee, PhD, professor of medicine and director of the San Diego LICR branch, and others noted that in GBMs only a minority of tumor cells possess a mutant form of the epidermal growth factor receptor (EGFR) gene. These cells drive the tumor's rapid, deadly growth. "Most GBM tumor cells express wild-type or normal EGFR," said Furnari. "Yet when expressed by itself, wild-type EGFR is a poor oncogene."

The scientists discovered that tumor cells with mutant EGFR secrete molecules that cause neighboring cells with wild-type EGFR to accelerate their tumorigenic growth. "The mutant cells are instructing other less malignant tumor cells to become more malignant," said Furnari.

This signaling pathway between GBM tumor cells was not known and presents a new and potentially promising chink in the armor of glioblastomas. "If we can inhibit or block this cellular communication, the tumor does not grow as quickly and may be more treatable," Furnari said. Researchers have already identified two molecules that appear to trigger EGFR activity on non-mutant tumor cells.

The findings may also provide clues in the bigger picture of how GBMs and other cancers survive and thrive. "There are other types of mutations and growth factor receptors in tumors," Furnari said. "We need to look at how they communicate. Historically, brain tumor research has focused upon the most abundantly expressed mutations, but this research suggests minority mutations play very important roles as well."

The researchers' next step will be to create a mouse model with mixed cell glioblastoma that can be used to test different therapeutics, inhibitors and blocking agents.

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